Pulmonary arterial hypertension incidence in Latvia in 2019

Pulmonary hypertension (PH) is a progressive pathophysiological disorder of abnormal elevation in pulmonary arterial blood pressure associated with poor prognosis. The clinical classification of PH is as follows: group 1— pulmonary arterial hypertension (PAH), group 2—PH due to left heart disease, group 3—PH due to lung disease and/or hypoxia, group 4—chronic thromboembolic PH, group 5—PH with unclear multifactorial mechanisms. PAH is a severe chronic cardiovascular condition caused by cellular proliferation and fibrosis of the small pulmonary arteries, resulting in a progressive increase in pulmonary vascular resistance (PVR). PAH is considered a rare disease with reported incidences of 7.1−15 cases per million inhabitants (MI).5–7 In agreement with the current PAH clinical classification, PAH can be classified as idiopathic, heritable, induced by drugs or toxins, or associated with conditions such as connective tissue disease (CTD), congenital heart disease (CHD), portal hypertension, HIV infection, or schistosomiasis. A definitive diagnosis of PAH requires hemodynamic demonstration at right heart catheterization of a mean pulmonary artery pressure (mPAP) ≥ 20mmHg, pulmonary artery wedge pressurE (PAWP) ≤ 15mmHg, and PVR>3 Wood units. Since the creation of the National Institutes of Health registry for patients with “primary” PH in 1981, crucial advances have been made in epidemiology of the different subgroups of PH.11–13 Despite the fact that extensive national and international registries have generated important information on the epidemiology as well as have improved diagnosis and management of PAH patients, regional discrepancies are undoubtedly present in patient characteristics, diagnostic workup, and treatment availability. Various studies have shown that despite the recent advancements in the field of PAH, belated diagnosis of PAH is still a significant issue.14–16 This highlights the necessity for more epidemiological data from nationwide registries, which take into account local specificities to achieve a more detailed global perspective of PAH. Thus, annual reports on the characteristics of PAH patients can demonstrate the dynamics of PAH patients year over year and try to help to identify recent trends and patterns. In this report, we present the incidence of PAH in Latvian adults in 2019 and their baseline characteristics including hemodynamics and exercise capacity.


INTRODUCTION
Pulmonary hypertension (PH) is a progressive pathophysiological disorder of abnormal elevation in pulmonary arterial blood pressure associated with poor prognosis. 1 The clinical classification of PH is as follows: group 1pulmonary arterial hypertension (PAH), group 2-PH due to left heart disease, group 3-PH due to lung disease and/or hypoxia, group 4-chronic thromboembolic PH, group 5-PH with unclear multifactorial mechanisms. 2 PAH is a severe chronic cardiovascular condition caused by cellular proliferation and fibrosis of the small pulmonary arteries, resulting in a progressive increase in pulmonary vascular resistance (PVR). 3,4 PAH is considered a rare disease with reported incidences of 7.1−15 cases per million inhabitants (MI). [5][6][7] In agreement with the current PAH clinical classification, PAH can be classified as idiopathic, heritable, induced by drugs or toxins, or associated with conditions such as connective tissue disease (CTD), congenital heart disease (CHD), portal hypertension, HIV infection, or schistosomiasis. 8,9 A definitive diagnosis of PAH requires hemodynamic demonstration at right heart catheterization of a mean pulmonary artery pressure (mPAP) ≥ 20 mmHg, pulmonary artery wedge pressurE (PAWP) ≤ 15 mmHg, and PVR > 3 Wood units. 10 Since the creation of the National Institutes of Health registry for patients with "primary" PH in 1981, crucial advances have been made in epidemiology of the different subgroups of PH. [11][12][13] Despite the fact that extensive national and international registries have generated important information on the epidemiology as well as have improved diagnosis and management of PAH patients, regional discrepancies are undoubtedly present in patient characteristics, diagnostic workup, and treatment availability. Various studies have shown that despite the recent advancements in the field of PAH, belated diagnosis of PAH is still a significant issue. [14][15][16] This highlights the necessity for more epidemiological data from nationwide registries, which take into account local specificities to achieve a more detailed global perspective of PAH. Thus, annual reports on the characteristics of PAH patients can demonstrate the dynamics of PAH patients year over year and try to help to identify recent trends and patterns.
In this report, we present the incidence of PAH in Latvian adults in 2019 and their baseline characteristics including hemodynamics and exercise capacity.

METHODS
This is a prospective, observational, study of the Latvian nationwide PH registry. All consecutive adult patients (≥18 years of age) recently diagnosed with PAH in the time period from January 1 to December 31, 2019 were included in the registry. A written informed consent for inclusion in the registry and publication of the study data was obtained from all patients after the nature of the study had been fully explained. This research was carried out in accordance with the 1975 Helsinki declaration (as revised in 2008). The diagnostic criteria for PAH patients were applied in accordance with latest 6th World Symposium on PH Task Force. 3 To confirm the diagnosis of PAH, right heart catheterization was performed, measuring right atrial pressure (RAP), mPAP, PAWP, PVR, cardiac output (CO) and cardiac index (CI). All identified PAH cases were categorized into PAH subtypes according to the clinical classification as follows: idiopathic, familial, or associated with anorexigen exposure, CTD, CHD, portal hypertension, or HIV infection. 8,9 The initial risk stratification of enrolled PAH patients was performed analyzing noninvasive parameters World Health Organization PAH classification, demographics, estimated glomerular filtration rate, New York Heart Association (NYHA) Functional class, heart rate, all-cause hospitalizations, systolic blood pressure, DLCO, 6-min walking distance (6MWD), B-type Natriuretic Peptide (BNP), echocardiography and two variables derived from the right heart catheterization (mean RAP [mRAP] and PVR). Patients were categorized as low, intermediate, or high risk, according to the method used by the Registry to Evaluate Early and Long-Term PAH Disease Management Registry (REVEAL) Risk Score 2.0. 17 Also, patient risk stratification was evaluated according to the european society of cardiology (ESC) simplified four-strata risk-assessment tool, evaluating World Health Organization Functional Classification (WHO-FC), 6MWD and BNP, categorizing PAH patients into low, intermediate-low, intermediate-high and high risk groups, according to the recent guidelines. 2 The obtained quantitative patient variables were described using mean, standard deviation (SD), minimum, and maximum.

RESULTS
A total of 23 PAH patients were included in the registry, where 6 patients were male and 17 were female. The female/male ratio was 2.83. In accordance with the World Health Organization PAH classification, out of 23 diagnosed PAH patients, 15 (65.21%) patients were idiopathic PAH, 4 (17.39%) patients with PAH associated with CHD, 2 (8.70%) patients-PAH associated with CTD, 1 (4.35%) patient-PAH associated with portal hypertension and 1 (4.35%) patient-PAH associated with HIV infection. Table 1 Table 2.
All of the 23 enrolled patients received PAH-specific monotherapy of phosphodiesterase type 5 inhibitors (Sildenafil). Regarding comorbidities, systemic arterial hypertension was the most prevalent (73.9%) underlying condition, which was followed by atrial fibrillation (56.5%). PAH patient comorbidities and received treatment at the time of the enrollment among study patients are shown in Table 3.
In 2019, the number of inhabitants in Latvia was 1.91 million, where 1.56 million were ≥18 years old (http:// data.csb.gov.lv, website accessed March 31, 2020). Thus, the estimated PAH incidence in Latvia in 2019 was 12.04 per MI and 14.74 per million adult inhabitants (MAI).

DISCUSSION
The present registry represents the data form the Latvian nationwide PH registry obtained in 2019, which was created in the September of 2007 at Pauls Stradiņš Clinical University Hospital in Riga.
A noticeable increase of over 60% was noted in PAH patient incidence in Latvia in 2019 comparing to the reported incidence from 2018, which was 7.2 per MI and 9.0 per MAI. 6  obtained results to a period of 2007-2016, where the PAH patient incidence in Latvia was 13.7 cases per MI, it is noted that overall, the PAH patient incidence has not increased, but fluctuates quite significantly year over year. 19 The obtained data showed a predominance of NYHA functional class III or IV in PAH patients, where 20 patients (86.96%) had a NYHA functional class III or IV. Although notable advances have been made in the PAH treatment, the data shows that most of the patients have severe symptoms at the time of enrollment, indicating late PAH diagnosis. The NYHA functional class is a critical predictor of outcome in PAH, thus it indicates that the awareness of PAH in the medical field is still insufficient. 20 Due to the varying incidence of different PH clinical groups, this study highlights the necessity for registries in each country or region of the world. 21 Better screening and characterization of PH patients in well-designed registries, which take into account local specificities, might enhance PAH detection and provide crucial information to health authorities. 21 To summarize, the coordination between European PH registries and specialist centers will result in earlier PH diagnosis and improved access to a specific therapy.

AUTHOR CONTRIBUTIONS
Ricards Kaulins takes responsibility for the content of the manuscript, including the data and analysis. Ainars Rudzitis, Aivars Lejnieks, Matiss Sablinskis, and Andris Skride were involved in study design, preparation of the draft manuscript, and critical revision and approval of the final manuscript.